Superficial fibrotic diatheses affect between 4-7% of the United States population. These conditions include Peyronie?s Disease (PD), which results in penile plaques and resulting curvature, Dupuytren?s Disease (DD), resulting in nodules of the palmar fasciae and hand contracture, and Ledderhose Disease (LD), causing scarring in the plantar aponeurosis. While considered benign, these conditions cause physical impairment and have significant psychological ramifications, negatively affecting relationships and causing depression. These superficial fibrotic diatheses can be heritable, co-existing in 15-22% of patients, and may be linked to other genetic conditions, including malignancy. Current treatments are incompletely effective, in part due to a limited understanding of the pathogenesis of fibrotic diatheses. The genetic factors predisposing to these conditions, and the molecular contributions of these factors to the pathogenesis of fibrotic diatheses have not been studied. Using a human forward-genetics screening approach, I identified microdeletions and microduplications involving genes implicated in inflammation and osteogenesis that may predispose to fibrotic plaque formation. I now seek to define the contributions of one of these genes, the secreted growth factor NELL1, to superficial fibrotic plaque formation. My preliminary data support a role for NELL1 in modulating signaling pathways involved in fibrosis and osteogenesis. Specifically, this proposal seeks support to dissect the roles of NELL1 in fibrosis and inflammation in fibrotic diatheses using in vitro assays and animal models. This basic research investigation addresses the hypothesis that NELL1 modulates signaling pathways involved in fibrosis and inflammation, and that alterations in gene dosage or function can predispose to aberrant collagen deposition and fibrotic plaque formation. The proposed work will define the impact of dosage and function of NELL1 on the above signaling pathways in fibroblasts derived from patients with PD and/or DD and from Nell1-deficient mice, as well as the impact on collagen deposition and fibrosis in vitro. These data will provide a detailed understanding of how NELL1 exerts its effects in aberrant fibrosis on a molecular level. The impact of Nell1 deficiency on penile and systemic fibrosis will be assessed using available Nell1-deficient mouse models to more definitively establish causality in the setting of genetic defects in these genes. This basic research study will define the role of NELL1 in the predisposition to fibrotic diatheses, laying the groundwork for understanding the spectrum of genetic lesions in superficial fibrotic diatheses. A thorough understanding of the genetic risk factors predisposing to fibrotic diatheses will permit improved diagnosis, risk stratification, and treatment in affected patients.